Diazabicyclooctane Compounds

ABSTRACT

The present invention relates to compounds according to Formula (II): 
     
       
         
         
             
             
         
       
     
     or a stereoisomer, tautomer or pharmaceutically acceptable salt or ester thereof, wherein A, R 1  and R 2  are defined herein. Also described are pharmaceutically acceptable compositions of Formula (II) compounds as well as methods for utilizing the compounds of Formula (II) and the pharmaceutically acceptable compositions of Formula (II) compounds as antibacterial agents and β-lactamase inhibitors, useful in the treatment of infectious diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No.62/405,332 filed Oct. 7, 2016, the contents of which are hereinincorporated by reference in their entirety.

ACKNOWLEDGMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Contract No.HHSO100201600038C awarded by the U.S. Department of Health and HumanServices. The government has certain rights in the invention.

FIELD

The present invention relates to compounds formed from the reaction ofoptically active diazabicyclooctane derivatives and β-lactams.

BACKGROUND

Penicillins and cephalosporins are β-lactam antibiotics that are widelyand frequently used in the clinic. However, the acquisition ofresistance to β-lactam antibiotics by various pathogens has had adamaging effect on maintaining the effective treatment of bacterialinfections. The most significant known mechanism related to theacquisition of bacterial resistance is the production of class A, C, andD β-lactamases having a serine residue at the active center. Theseenzymes decompose the β-lactam antibiotic, resulting in the loss of theantimicrobial activities. Class A β-lactamases preferentially hydrolyzepenicillins while class C β-lactamases have a substrate profile favoringcephalosporins.

Commercially available β-lactamase inhibitors, e.g., clavulanic acid,sulbactam, and tazobactam, are known inhibitors effective mainly againstclass A β-lactamase producing bacteria, and are used as a mixture with aβ-lactam antibiotic. However, many hundreds or more of β-lactamases havebeen reported to date, including those from resistant bacteria whichproduce class A KPC-2 β-lactamase decomposing even carbapenems.

In recent years, infectious diseases caused by the above-mentionedresistant bacteria as pathogenic bacteria are found not only in severeinfectious disease but also occasionally in community-acquiredinfectious disease. The currently available antibiotics and β-lactamaseinhibitors are progressively becoming ineffective against theincessantly increasing activities of constantly mutating bacterialβ-lactamases and as such novel β-lactamase inhibitors and otherantibacterial agents are required for the demanding treatment ofinfectious diseases caused by resistant bacteria.

SUMMARY

The invention is directed to antibacterial agents and β-lactamaseinhibitors, useful in the treatment of infectious diseases.

The invention is also directed to a β-lactamase inhibitor effective forthe β-lactamase producing bacteria, particularly for the class A, classC and class D β-lactamases. In one embodiment the β-lactamase inhibitormay also recover the antimicrobial activity of a β-lactam antibioticagainst the resistant bacteria when used in combination with theβ-lactam antibiotic.

In one embodiment the invention is directed to an antibacterial agent orβ-lactamase inhibitor that is a compound formed between a reaction of acompound of Formula (I) and a β-lactam, wherein Formula (I) is

wherein

R¹ is benzyl, H or SO₃M; and

M is H, an inorganic cation or an organic cation, or a pharmaceuticallyacceptable salt or ester thereof.

In one embodiment, R¹ is SO₃M, wherein M is H.

In another embodiment the β-lactam is a β-lactam antibiotic andcomprises a core selected from penam, carbapenam, oxapenam, penem,carbapenem, monobactam, cephem, carbacephem and oxacephem.

In another embodiment the β-lactam antibiotic is selected fromampicillin, amoxicillin, azidocillin, azlocillin, aztreonam, biapenem,carbeniccilin, carfecillin, carindacillin, carumonam, cefepime,cefotaxim, cefsumide, ceftaroline, ceftolozane ceftriaxone, ceftazidime,cephem, doripenem, ertapenem, flomoxef, meropenem, piperacillin,tazobactam, ticarcillin, and tigermonam, or pharmaceutically acceptablesalts or esters thereof.

In yet another embodiment the β-lactam antibiotic is meropenem, or apharmaceutically acceptable salt or ester thereof.

In another aspect the present invention is directed to a compound ofFormula (II):

wherein

R¹ is benzyl, H or SO₃M;

M is H, or an inorganic or organic cation;

R² is H, (C₁-C₈)alkyl, —NHC(O)CH₂-aryl, —NHC(O)CH₂-heteroaryl,—NHC(O)CH(NH₂)-aryl or —NHC(O)(CH₂)₃CH(NH₂)—CO₂R³;

A is a 5- to 6-membered heterocyclic ring containing at least onenitrogen atom and substituted with one or more groups selected fromhalogen, CN, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, OR³, NR³R³, C(O)R³, [(C₁-C₈)alkylene]OR³,[(C₁-C₈)alkylene]OC(O)R³, [(C₁-C₈)alkylene]OC(O)NR³R³,[(C₁-C₈)alkylene]NR³R³, C(O)NR³R³, C(O)[(C₁-C₈)alkylene]NR³R³, CO₂R³,C(S)NR³R³, SR³, S(O)R³, SO₂R³ and SO₂NR³R³;

R³ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl, cycloalkyl,heterocyclyl, [(C₁-C₈)alkylene]heterocyclyl, aryl, [(C₁-C₈)alkylene]arylor heteroaryl; and

wherein any alkyl, cycloalkyl, heterocyclyl, heteroaryl or aryl isoptionally substituted with 1, 2, or 3 groups selected from OH, CN, SH,SO₂NH₂, halogen, NH₂, NHCNH, C(O)NH₂, C(O)N(CH₃)₂, C(O)NH(aryl-COOH),C(NH)CH₃, CH₂(NH)SO₂NH₂, COOH, COOCH₃, acetyl, (C₁-C₈)alkyl,O(C₁-C₈)alkyl, S(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₁-C₈)haloalkyl, (C₁-C₈)thioalkyl and heterocyclyl.

In one embodiment R¹ is SO₃M.

In one embodiment R² is (C₁-C₈)alkyl.

In one embodiment A is a 5-membered heterocyclic ring containing onenitrogen atom. In another embodiment A is a 5-membered heterocyclic ringcontaining one nitrogen atom and one oxygen atom. In another embodimentA is a 5-membered heterocyclic ring containing one sulfur atom.

In one embodiment A is a 5-membered heterocyclic ring containing onenitrogen atom and substituted with (C₁-C₈)alkyl, COOH or SR³, wherein R³is heterocyclyl.

In one embodiment a compound of Formula (II) is

or a pharmaceutically acceptable salt or ester thereof.

In another embodiment compositions are disclosed comprising a compoundof Formula (II) in combination with a pharmaceutically acceptablecarrier, diluent or excipient.

The compounds are useful in the treatment of bacterial infections inhumans or animals either alone or in combination with β-lactamantibiotics and/or with other non β-lactam antibiotics.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. Unless the contextrequires otherwise, throughout the present specification and claims, theword “comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense (i.e., as“including, but not limited to”).

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Definitions

As used herein, and unless noted to the contrary, the following termsand phrases have the meaning noted below.

“Amino” refers to the —NH₂ substituent.

“Aminocarbonyl” refers to the —C(O)NH₂ substituent.

“Carboxyl” refers to the —CO₂H substituent.

“Carbonyl” refers to a —C(O)— or —C(═O)— group. Both notations are usedinterchangeably within the specification.

“Cyano” refers to the —C≡N substituent.

“Cyanoalkylene” refers to the -(alkylene)C≡N substituent.

“Acetyl” refers to the —C(O)CH₃ substituent.

“Hydroxy” or “hydroxyl” refers to the —OH substituent.

“Oxo” refers to an oxygen of —O— substituent.

“Alkyl” refers to a saturated, straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms (C₁-C₁₂ alkyl), from one to eight carbon atoms(C₁-C₈ alkyl) or from one to six carbon atoms (C₁-C₆ alkyl), and whichis attached to the rest of the molecule by a single bond. Exemplaryalkyl groups include methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like.

“Lower alkyl” has the same meaning as alkyl defined above but havingfrom one to four carbon atoms (C₁-C₄ alkyl).

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon (alkyl) chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, respectively. Alkylenescan have from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single or double bond. The points ofattachment of the alkylene chain to the rest of the molecule can bethrough one carbon or any two carbons within the chain. “Optionallysubstituted alkylene” refers to alkylene or substituted alkylene.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl having the indicated number of carbon atoms as defined above.Examples of alkoxy groups include without limitation —O-methyl(methoxy), —O-ethyl (ethoxy), —O-propyl (propoxy), —O-isopropyl (isopropoxy) and the like.

“Acyl” refers to a radical of the formula —C(O)R_(a) where R_(a) is analkyl having the indicated number of carbon atoms.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls arehydrocarbon ring system radical comprising hydrogen and 6 to 9 carbonatoms and at least one aromatic ring; hydrocarbon ring system radicalcomprising hydrogen and 9 to 12 carbon atoms and at least one aromaticring; hydrocarbon ring system radical comprising hydrogen and 12 to 15carbon atoms and at least one aromatic ring; or hydrocarbon ring systemradical comprising hydrogen and 15 to 18 carbon atoms and at least onearomatic ring. For purposes of this invention, the aryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Aryl radicals include, but arenot limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. “Optionally substituted aryl” refers to an aryl group or asubstituted aryl group.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,three to nine carbon atoms, three to eight carbon atoms, three to sevencarbon atoms, three to six carbon atoms, three to five carbon atoms, aring with four carbon atoms, or a ring with three carbon atoms. Thecycloalkyl ring may be saturated or unsaturated and attached to the restof the molecule by a single bond. Monocyclic radicals include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo (bromine), chloro (chlorine), fluoro(fluorine), or iodo (iodine).

“Haloalkyl” refers to an alkyl radical having the indicated number ofcarbon atoms, as defined herein, wherein one or more hydrogen atoms ofthe alkyl group are substituted with a halogen (halo radicals), asdefined above. The halogen atoms can be the same or different. Exemplaryhaloalkyls are trifluoromethyl, difluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Heterocyclyl”, heterocycle”, or “heterocyclic ring” refers to a stable3- to 18-membered saturated or unsaturated radical which consists of twoto twelve carbon atoms and from one to six heteroatoms, for example, oneto five heteroatoms, one to four heteroatoms, one to three heteroatoms,or one to two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Exemplary heterocycles include withoutlimitation stable 3-15 membered saturated or unsaturated radicals,stable 3-12 membered saturated or unsaturated radicals, stable 3-9membered saturated or unsaturated radicals, stable 8-membered saturatedor unsaturated radicals, stable 7-membered saturated or unsaturatedradicals, stable 6-membered saturated or unsaturated radicals, or stable5-membered saturated or unsaturated radicals.

Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of non-aromatic heterocyclyl radicals include, butare not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclylsinclude heteroaryls as defined herein, and examples of aromaticheterocyclyls are listed in the definition of heteroaryls below.

“Heteroaryl” or “heteroarylene” refers to a 5- to 14-membered ringsystem radical comprising hydrogen atoms, one to thirteen carbon atoms,one to six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur, and at least one aromatic ring. For purposes of thisinvention, the heteroaryl radical may be a stable 5-12 membered ring, astable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8membered ring, a stable 5-7 membered ring, or a stable 6 membered ringthat comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. The heteroatom may be a member of an aromatic ornon-aromatic ring, provided at least one ring in the heteroaryl isaromatic. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl).

“Sulfoxide” refers to a —S(O)— group in which the sulfur atom iscovalently attached to two carbon atoms.

“Sulfone” refers to a —S(O)₂— group in which a hexavalent sulfur isattached to each of the two oxygen atoms through double bonds and isfurther attached to two carbon atoms through single covalent bonds.

The compound of the invention can exist in various isomeric forms, aswell as in one or more tautomeric forms, including both single tautomersand mixtures of tautomers. The term “isomer” is intended to encompassall isomeric forms of a compound of this invention, including tautomericforms of the compound.

Some compounds described here can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A compound ofthe invention can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses compounds of the invention andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the invention can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography, orvia chemical separation of stereoisomers through the employment ofoptically active resolving agents.

Unless otherwise indicated, “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

In this description, a “pharmaceutically acceptable salt” is apharmaceutically acceptable, organic or inorganic acid or base salt of acompound of the invention. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The terms “treat”, “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with an infectiousdisease. In certain embodiments, such terms refer to minimizing thespread or worsening of the infectious disease resulting from theadministration of one or more prophylactic or therapeutic agents to apatient with such a infectious disease.

The term “effective amount” refers to an amount of a compound of theinvention or other active ingredient sufficient to provide a therapeuticor prophylactic benefit in the treatment or prevention of an infectiousdisease or to delay or minimize symptoms associated with an infectiousdisease. Further, a therapeutically effective amount with respect to acompound of the invention means that amount of therapeutic agent alone,or in combination with other therapies, that provides a therapeuticbenefit in the treatment or prevention of an infectious disease. Used inconnection with a compound of the invention, the term can encompass anamount that improves overall therapy, reduces or avoids symptoms orcauses of disease, or enhances the therapeutic efficacy or synergieswith another therapeutic agent.

A “patient” or subject” includes an animal, such as a human, cow, horse,sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig. The animal can be a mammal such as a non-primate and aprimate (e.g., monkey and human). In one embodiment, a patient is ahuman, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug that is a compoundwhich upon administration to a patient must undergo chemical conversionby metabolic processes before becoming an active pharmacological agent.Exemplary prodrugs of compounds in accordance with Formula (II) areesters, acetamides, and amides.

The inventive compounds according to Formula (II) may beisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of according to Formula (II) includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, or iodine. Illustrative of such isotopes are ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabelled compounds can be used to measure thebiodistribution, tissue concentration and the kinetics of transport andexcretion from biological tissues including a subject to which such alabelled compound is administered. Labeled compounds are also used todetermine therapeutic effectiveness, the site or mode of action, and thebinding affinity of a candidate therapeutic to a pharmacologicallyimportant target. Certain radioactive-labelled compounds according toFormula (I), therefore, are useful in drug and/or tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, affordscertain therapeutic advantages resulting from the greater metabolicstability, for example, increased in vivo half-life of compoundscontaining deuterium. Substitution of hydrogen with deuterium may reducedose required for therapeutic effect, and hence may be preferred in adiscovery or clinical setting.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, provides labeled analogs of the inventive compounds that are usefulin Positron Emission Tomography (PET) studies, e.g., for examiningsubstrate receptor occupancy. Isotopically-labeled compounds accordingto Formula (II) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples section as set out belowusing an appropriate isotopic-labeling reagent.

Embodiments of the invention disclosed herein are also meant toencompass the in vivo metabolic products of compounds according toFormula (II). Such products may result from, for example, the oxidation,reduction, hydrolysis, amidation, esterification, and like processesprimarily due to enzymatic activity upon administration of a compound ofthe invention. Accordingly, the invention includes compounds that areproduced as by-products of enzymatic or non-enzymatic activity on aninventive compound following the administration of such a compound to amammal for a period of time sufficient to yield a metabolic product.Metabolic products, particularly pharmaceutically active metabolites aretypically identified by administering a radiolabelled compound of theinvention in a detectable dose to a subject, such as rat, mouse, guineapig, monkey, or human, for a sufficient period of time during whichmetabolism occurs, and isolating the metabolic products from urine,blood or other biological samples that are obtained from the subjectreceiving the radiolabelled compound.

The invention also provides pharmaceutically acceptable salt forms ofFormula (II) compounds. Encompassed within the scope of the inventionare both acid and base addition salts that are formed by contacting apharmaceutically suitable acid or a pharmaceutically suitable base witha compound of the invention.

To this end, a “pharmaceutically acceptable acid addition salt” refersto those salts which retain the biological effectiveness and propertiesof the free bases, which are not biologically or otherwise undesirable,and which are formed with inorganic acids such as, but are not limitedto, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

Similarly, a “pharmaceutically acceptable base addition salt” refers tothose salts which retain the biological effectiveness and properties ofthe free acids, which are not biologically or otherwise undesirable.These salts are prepared by addition of an inorganic base or an organicbase to the free acid. Salts derived from inorganic bases include, butare not limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compounds of the invention may be truesolvates, while in other cases, the compounds of the invention maymerely retain adventitious water or be a mixture of water plus someadventitious solvent.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

Compounds of the invention, or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule.

The inventive compounds are synthesized using conventional syntheticmethods, and more specifically using the general methods noted below.Specific synthetic protocols for several compounds in accordance withthe present invention are described in the Examples.

Pharmaceutical Formulations

In one embodiment, a compound according to Formula (II) is formulated aspharmaceutically acceptable compositions that contain a Formula (II)compound in an amount effective to treat a particular disease orcondition of interest upon administration of the pharmaceuticalcomposition to a mammal. Pharmaceutical compositions in accordance withthe present invention can comprise a Formula (II) compound incombination with a pharmaceutically acceptable carrier, diluent orexcipient.

In this regard, a “pharmaceutically acceptable carrier, diluent orexcipient” includes without limitation any adjuvant, carrier, excipient,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

Further, a “mammal” includes humans and both domestic animals such aslaboratory animals and household pets (e.g., cats, dogs, swine, cattle,sheep, goats, horses, rabbits), and non-domestic animals such aswildlife and the like.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition is preferably in eithersolid or liquid form, where semi-solid, semi-liquid, suspension and gelforms are included within the forms considered herein as either solid orliquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfite; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by anymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

Therapeutic Use

The compounds of the invention, or their pharmaceutically acceptablesalts or esters, are administered in a therapeutically effective amount,which will vary depending upon a variety of factors including theactivity of the specific compound employed; the metabolic stability andlength of action of the compound; the age, body weight, general health,sex, and diet of the patient; the mode and time of administration; therate of excretion; the drug combination; the severity of the particulardisorder or condition; and the subject undergoing therapy.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment of aninfectious disease in the mammal. The amount of a compound of theinvention which constitutes a “therapeutically effective amount” willvary depending on the compound, the condition and its severity, themanner of administration, and the age of the mammal to be treated, butcan be determined routinely by one of ordinary skill in the art havingregard to his own knowledge and to this disclosure.

Compounds of the invention, or pharmaceutically acceptable salts oresters thereof, may also be administered simultaneously with, prior to,or after administration of one or more other therapeutic agents. Suchcombination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of the invention and one ormore additional active agents, as well as administration of the compoundof the invention and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of theinvention and the other active agent can be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent administered in separate oral dosageformulations. Where separate dosage formulations are used, the compoundsof the invention and one or more additional active agents can beadministered at essentially the same time, i.e., concurrently, or atseparately staggered times, i.e., sequentially; combination therapy isunderstood to include all these regimens.

Therapeutically effective dosages of a compound according to Formula(II) or a composition of a Formula (II) compound will generally rangefrom about 1 to 2000 mg/day, from about 10 to about 1000 mg/day, fromabout 10 to about 500 mg/day, from about 10 to about 250 mg/day, fromabout 10 to about 100 mg/day, or from about 10 to about 50 mg/day. Thetherapeutically effective dosages may be administered in one or multipledoses. It will be appreciated, however, that specific doses of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated, timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

The term “β-lactam antibiotic” refers to a compound with antibioticproperty that contains a β-lactam functionality. Examples of β-lactamantibiotics which can be used in combination with the compounds of thepresent invention represented by formula (II) are commonly marketedpenicillins, cephalosporins, penems, carbapenems and monobactams.

Examples of β-lactam antibiotics which can be used in combination withthe compounds of the present invention represented by formula (II) arecommonly used penicillins, such as amoxicillin, ampicillin, azlocillin,mezlocillin, apalcillin, hetacillin, bacampicillin, carbenicillin,sulbenicillin, ticarcillin, piperacillin, methicillin, ciclacillin,talampicillin, oxacillin, cloxacillin, dicloxacillin and commonly usedcephalosporins such as cephalothin, cephaloridine, cefaclor, cefadroxil,cefamandole, cefazolin, cephalexin, cephradine, cephapirin, cefuroxime,cefoxitin, cephacetrile, cefotiam, cefotaxime, cefatriazine, cefsulodin,cefoperazone, ceftizoxime, cefmenoxime, cefmetazole, cephaloglycin,cefonicid, cefodizime, cefpirome, cefepime, ceftazidime, cefpiramide,ceftriaxone, cefbuperazone, cefprozil, cefixime, ceftobiprole,ceftaroline, cefalonium, cefminox, ceforanide, cefuzonam, cefoxitin,cefotetan, loracarbef, cefdinir, cefditoren, cefetamet, cefcapene,cefdaloxime, ceftibuten, cefroxadine, latamoxef (moxalactam), andCXA-101. From the carbapenem class of β-lactam antibiotics such asimipenem, meropenem, panipenem, biapenem, doripenem, ertapenem and thelike could be used. From monobactam class of β-lactam antibiotics suchas aztreonam, carumonam, tigemonam, and the like could be used as thecombination partner of antibiotic.

Synthesis

The following examples are provided for purpose of illustration and notlimitation.

EXAMPLE 1(4R,5S)-3-(((3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl)thio)-5-((2S,3R)-3-hydroxy-1-oxo-1-((2-(((2S,5R)-7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1]octane-2-carboxamido)oxy)ethyl)amino)butan-2-yl)-4-methyl-4,5-dihydro-1H-pyrrole-2-carboxylicacid

In a 50 ml round-bottomed flask equipped with a with rubber seal,(4R,5S,6S)-3-(((3S,5S)-5-(dimethylcarbamoyl)pyrrolidin-3-yl)thio)-6-((R)-1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid or meropenem (Reactant (a), 924 mg, 2.41 mmol), which containssodium carbonate (383 mg, 3.61 mmol), was dissolved in water (13 ml)rendering a solution having a pH value of ˜8. To this solution,(2S,5R)-2-((2-aminoethoxy)carbamoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-ylhydrogen sulfate hydrate (Reactant (b), 1.31 g, 3.83 mmol) was added inone portion. A white suspension that was initially formed from themixing of Reactant (a) and Reactant (b) was stirred at room temperaturefor 40 h, during which a clear brown solution was formed.

The reaction solvent was removed by lyophilization at ≦room temperatureover a period of ca. 20 h to maintain mild conditions. The crude productwas recovered as a brown powder, 2.33 g, in 137% yield. HPLC (area %):14% Reactant (b)+38% Product (c)+8% unknown. The remaining area % wasdistributed in broad peaks.

A 540 mg aliquot of the crude product aliquot was subjected to apreparative HPLC run. Fractions containing product were collected,combined & freed of solvent by lyophilization at ≦room temperature for aperiod of over 24 h, furnishing 120 mg of Product (c), a white, wispyweb-like material. HPLC (area %): 96%, ¹H-NMR correlates with referencesample.

Antibacterial Activity

Compounds of the present invention, either alone or in combination withone or more antibiotics, are tested for minimum inhibitory concentration(MIC, μg/mL) against various bacteria. Compounds of the presentinvention can also be tested in combination with various antibioticsagainst metallo β-lactamase producing bacteria.

β-Lactamase Inhibitory Activity

The inhibitory activities of present compounds against various enzymesare measured by spectrophotometric assay using 490 nM and usingnitrocefin as a substrate [J. Antimicrob. Chemother., 28, pp 775-776(1991)]. The concentration of inhibitor (IC₅₀) which inhibits by 50% thereaction of hydrolysis of nitrocefin by the enzyme is determined.

The various embodiments described above can be combined to providefurther embodiments. Aspects of the embodiments can be modified, ifnecessary to employ concepts of the various patents, applications andpublications to provide yet further embodiments. These and other changescan be made to the embodiments in light of the above-detaileddescription. In general, in the following claims, the terms used shouldnot be construed to limit the claims to the specific embodimentsdisclosed in the specification and the claims, but should be construedto include all possible embodiments along with the full scope ofequivalents to which such claims are entitled. Accordingly, the claimsare not limited by the disclosure.

1. A compound formed between a reaction of a compound of Formula (I) anda β-lactam, wherein Formula (I) is

wherein R¹ is benzyl, H or SO₃M; and M is H, an inorganic cation or anorganic cation, or a pharmaceutically acceptable salt or ester thereof.2. The compound of claim 1 wherein R¹ is SO₃M, wherein M is H.
 3. Thecompound of claim 1 wherein the β-lactam is a β-lactam antibiotic andcomprises a core selected from penam, carbapenam, oxapenam, penem,carbapenem, monobactam, cephem, carbacephem and oxacephem.
 4. Thecompound of claim 3 wherein the β-lactam antibiotic is selected fromampicillin, amoxicillin, azidocillin, azlocillin, aztreonam, biapenem,carbeniccilin, carfecillin, carindacillin, carumonam, cefepime,cefotaxim, cefsumide, ceftaroline, ceftolozane ceftriaxone, ceftazidime,cephem, doripenem, ertapenem, flomoxef, meropenem, piperacillin,tazobactam, ticarcillin, and tigermonam, or pharmaceutically acceptablesalts or esters thereof.
 5. The compound of claim 4 wherein the β-lactamantibiotic is meropenem, or a pharmaceutically acceptable salt or esterthereof.
 6. A compound of Formula (II)

wherein R¹ is benzyl, H or SO₃M; M is H, or an inorganic or organiccation; R² is H, (C₁-C₈)alkyl, —NHC(O)CH₂-aryl, —NHC(O)CH₂-heteroaryl,—NHC(O)CH(NH₂)-aryl or —NHC(O)(CH₂)₃CH(NH₂)—CO₂R³; A is a 5- to6-membered heterocyclic ring containing at least one nitrogen atom andsubstituted with one or more groups selected from halogen, CN,(C₁-C₈)alkyl, (C₁-C₈)haloalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, OR³,NR³R³, C(O)R³, [(C₁-C₈)alkylene]OR³, [(C₁-C₈)alkylene]OC(O)R³,[(C₁-C₈)alkylene]OC(O)NR³R³, [(C₁-C₈)alkylene]NR³R³, C(O)NR³R³,C(O)[(C₁-C₈)alkylene]NR³R³, CO₂R³, C(S)NR³R³, SR³, S(O)R³, SO₂R³ andSO₂NR³R³; R³ is independently H, (C₁-C₈)alkyl, (C₁-C₈)haloalkyl,cycloalkyl, heterocyclyl, [(C₁-C₈)alkylene]heterocyclyl, aryl,[(C₁-C₈)alkylene]aryl or heteroaryl; and wherein any alkyl, cycloalkyl,heterocyclyl, heteroaryl or aryl is optionally substituted with 1, 2, or3 groups selected from OH, CN, SH, SO₂NH₂, halogen, NH₂, NHCNH, C(O)NH₂,C(O)N(CH₃)₂, C(O)NH(aryl-COOH), C(NH)CH₃, CH₂(NH)SO₂NH₂, COOH, COOCH₃,acetyl, (C₁-C₈)alkyl, O(C₁-C₈)alkyl, S(C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₁-C₈)haloalkyl, (C₁-C₈)thioalkyl and heterocyclyl, ora pharmaceutically acceptable salt or ester thereof.
 7. The compound ofclaim 6 wherein R¹ is SO₃M.
 8. The compound of claim 6 wherein R² is(C₁-C₈)alkyl.
 9. The compound of claim 6 wherein A is a 5-memberedheterocyclic ring containing one nitrogen atom.
 10. The compound ofclaim 6 wherein A is a 5-membered heterocyclic ring containing onenitrogen atom and one oxygen atom.
 11. The compound of claim 6 wherein Ais a 5-membered heterocyclic ring containing one sulfur atom.
 12. Thecompound of claim 6 wherein A is a 5-membered heterocyclic ringcontaining one nitrogen atom and substituted with (C₁-C₈)alkyl, COOH orSR³, wherein R³ is heterocyclyl.
 13. The compound of claim 6 that is

or a pharmaceutically acceptable salt or ester thereof.
 14. Apharmaceutical composition comprising a compound of Formula (II) incombination with a pharmaceutically acceptable carrier, diluent orexcipient.
 15. A method for treating a bacterial infection in a mammalin need thereof comprising administrating to the mammal (i) atherapeutically effective amount of at least one compound according toclaim 1 or a stereoisomer, tautomer or pharmaceutically acceptable saltor ester thereof, or (ii) a pharmaceutical composition of claim 14.